Thermal injury following burns is a common clinical condition. Excessive systemic inflammatory response syndrome (SIRS) following burns leads to distant organ damage and multiple organ dysfunction syndrome (MODS). Development of in vivo experimental models of burns over the past 50 years have facilitated the study of the effects of thermal injury on physiological and immunological parameters in the pathogenesis of burns and associated systemic organ damage. Using these models, researchers have established the critical role played by inflammatory mediators such as TNF-α, IL-1β, IL-6, IL-2 and substance P in burns and associated systemic organ damage. The rationale of this chapter is to present an overview of different experimental animal models, both rodents as well as large animals, of burns and associated SIRS and the role of inflammatory mediators in the pathogenesis of this condition as well as in pathogenesis of the resultant MODS.